Preparation of 1, 2, 4-oxadiazoles



Patented July 9, 1946 1 UNITED STATES OFFICE PREPARATION F1,2,4-0XADIAZOLES I Donald Kaisegrl tiverside, 00ml, assignor to American Cyanamld Company, New York, N. Y.,acorporation oll tialn'e. V U 7 No Drawing. Application June 23, 1944, Serial N0. 541,845

pounds, nove1 'reaction products thereof, and to In; the formulas R; is analkyl, .cycl'oalkyl, or. aryl radical; The products of the reaction, .3-alky1, cycloalkyl, are Knew compounds and form .the .principalsube iect 'matter of the I present invention. 1 Theamino group'i-si very. easily hydrolyzed to a, .OH group, and" the resulting compounds, ..3-'alkyl,

are also new compounds and are included within the purview of the present invention- .These' latter' compounds are easily formed upon. continued hydrolysisofthe reaction mixture.

Ihe hydrolysis of-3'-'alkyl, cycloalkyl, and aryl- 5-'ureid'o-1-,2,4-oxadiazoles may take place at temperatures between about'25--C'.: and 125 C. in an alkaline or acidic reaction medium comprising water. A convenient'meth'od ofconduct ing the reaction is to mix the reactants ina suitable solvent or diluent and heat the reaction'mixture under a reflux condenser until the reaction is complete. This maybe determined by trapping the ammonia evolved from the reaction mixture and determining the amount so evolved until a theoretical quantity has been liberated. This procedure is illustrated in one :of thesp'ecific exampleshereinafter described. a I.

The time required-to complete the reaction may be from about 1 hour to about 30 hours or more depending upon the temperatureofthe reaction and the nature of the acid or alkaliemployed as the hydrolyzing agent. e

A suitable solvent for the reactants may be water alone or ethanol, methanol, butanol, dioxane, Cellosolve, or otherwater-miscible solvent, or a mixture or-these solvents with each other or with water.- It will be understood, of

7 Claims. (01. zoo-307i as solution Willtake Pl c a h time after the reaction has startedv.

'The 3-a1ky1, cycloalkyl, and aryl-B-ureido- 1,2, l-oxadiazoles which are u ed as intermediates in the present invention can be prepared-by heating together an acyl dicyandiamide and hy- Y droxylamine, as shown in Example 1 The acyl v dicyandiamides are in turn prepared bysimply mixingdicyandiamide with a desired acyl halide oranhydride in a water-soluble alkali metal hydroxide in the presence of a small amount of and aryl-S-amino-1,2,4-oxadiazoles,

water and a nonehydroxylated solvent such as acetone. p

.Agreatnumber of 3-alkyl, cycloalkyl, and aryl- 5-.ureido-1,2,4-oxadiazoles can be employed in the. reaction describedherein to produce the new compounds 1 of the. present, invention. Among these. may be specifically mentioned: 3-methyl- 5-ureido-1,2,4-oxadiazole, 3-n-butyl-5-ureido- 1,2,4-oxadiazole, 3-isoamyl 5-ureido-1,2,4 oxadiazole, .3=dodecyle5-ureidoe1,2,4-oxadiazole, ,3-

L-Almost any commonly used acidic or alkaline hydrolyzing agent may be used in the process de scribed herein; Among such conventional hydrolyzing agents are sodium. hydroxide, potassium. hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, barium hydroxide; etc, and sulfuric acid, hydrochloric acid, acetic acid, nitric acid, phosphoric acid, etc. Since the use of acidic and alkaline hydrolyzing agents is well understood. by thosein the art, lure ther'de'soription thereof would. appear to be unnecessary. a

course-that, enoughwater is present to enable The. 3'-alkyl, cycloalkyl, and ary1-5-amino- 1,2,4-oxadiazoles of the present invention are generally characterized as being basic, white crystalline solids, easily to slightly soluble in Water depending upon the nature of the 3-substituent. In general, they are not easily soluble in organic solvents but may be dissolved in mall amounts in Cellosolve, aliphatic alcohols, pyridine, dloxane, etc, They melt or decompose at high temperatures, their melting points being somewhat dependent upon th manner in which they are determined; The 3-alky1, cycloalkyl, and

aryl:5-amino-l,2,l-oxadiazoles are useful for a variety of purposes including: as ,dyestuif intermediates, in the preparation of'ch'emotherapeutic agents, in. the preparation of 1 quaternary ammonium-compounds, and the like..

cal properties to the 5-amino-oxadiazoles but are characterized as being slightly more soluble in water and having a higher melting or decomposition point.

As previously stated, the 5-amino-oxadiazoles are easily converted to the correspondingb-hy droxy-oxadiazoles upon continued 'hydrolysis;

and care must be exercised in the initial hydrolysis if good yields of the -amino oxadiazoles; are 3 to be obtained. Also, as previously mentioned,

the course of the reaction may be followed and stopped at the required point by observing the amount of ammonia evolved from the reaction mixture. Continued hydrolysis results in elimination of an additional mole of ammonia through replacement of the 5-amino'group-by-a hydroxy group iii the presence or water; g

My invention will now be illustratedin greater} detail by means of the following specific exampleswhich are given for purposes of illustration and are not'to be considered as limiting my invention to the particular details described therein.

' Example} To a suspension of 131.6 g. ofbenzoyl dicyandiamide in 1500 cc. of water was added a solution of 59 g. of hydroxylamine hydrochloride in .1500 cc. of water. i The mixture was stirred and heated and anadditional 500 cc. of water added. Afte r refluxing minutes, the mixture was cooled andthe colorless solid filtered. washed with water, and dried. On analysis itproved to be 3phenyl- 5-ureido-1,2,4-0xadiazole. v y I L To'a solution-of 33 g. (0.50 mol) of 85%potas sium hydroxide in 250 cc. of water was added 40.8 g. (0.20 mol) of 3-phenyl-5-ureido-1,2,4- oxadiazole. On heating to reflux, solution oc-. curred, and ammonia began to be evolved. After. 2 hours of heating, Nuchar was added tothe light yellow solution, and it was then filtered. Cooling of the nearly colorless filtrate gave a small quantity of long needles which melted at 160-162 C. Crystallization from a'large volume of hot water gave slender, beautiful needles which .meltedat 164-165" C. and which analyzed correctly 011.3- phenyl 5 1 amino-1,2,4-oxadiazole. Thisjlzcompound was soluble in acid,.rreprecipitated .by alkali, and insoluble in excess alkali. When; a portion was dissolved inwater which contained silver nitrate, addition of a dropof ammonia precipitated a light, yellow, amorphous, silver salt which decomposed at 192 C. 0. Addition of acetic acid to the original alkaline filtrate, obtained from the reaction immediately above, precipitated, 20 g. of colorless solid which decomposed at 188-190 C. Crystallization from a large volume of water which contained alittle methanol raised the decomposition point to 19'l198 C. The material was alkali soluble, reprecipitated by acids, andinsolublezin excess acid. Analysis wasin good agreement vfor. 3- phenyl-5-hydroxy-1,2,4-oxadiazole.

Example 2 In a further experiment using barium hydrox ide in place of potassium hydroxide the mixture was refluxed for 17'hours. After separating the barium carbonate which had formed'in the reaction mixture, 3-phenyl-5-amino-1,2,4 0Xadiazole was recovered. No." 3-phenyl-5-hydrbxy- 1,2,4-oxadiazo1ewas obtained when using' this mild hydrolyzingagent underthe conditions of this experiment.-- 1

Example 3; 7 "A solution of 32.5 g. of 97 barium hydroxide octahydrate in 250 cc. of hot water was filtered and added to 24.4 g. of 3-methyl-5-ureido-1,2,4-

: oxadiazole in a 1-liter flask fitted with a stirrer,

nitrogen bubbling tube, and a condenser leading to a,-,safety bottle and finally to an absorption flask containing cc. of 2.5 N hydrochloric acid. A stream of nitrogen was passed into the reaction mixture as the mixture was refluxed gently. The rate and extent of reaction was followed by titrating the acid solution to determine the amount of ammonia evolved and by weighing the barium carbonate precipitated during the reaction. The reaction was completed in 14 hours and.15 minutes. The reaction mixture'rwasfflltered .andcooled in an ice bath to precipitate awhitesolid. By continuous .ether, extractionv of this'solid" and the'mother liquor "a total of 11.2 g; ofglassy needles melting at 160-162 C. wasv obtained; ,By recrystallizing a sample of 1. g. of this'product from 200 cc. .of ether, a sample, meltingiat 163-164 C." was obtained which analyzed cor- 1 rectly for 3-methyl-5-amino-1,2,4-oxadiazole.

A mixture of 20.4 g. (0.10 mol).-of 3-.phenyl-5- ureido-1,2,4-oxadiazole, 60 g. (0.60 mol) of concentrated hydrochloric acid, 250 cc. of water, and

cc. of dioxanewas heated to reflux. The mixture foamed, and more dioxane and some butanol were added, After an hours heating, solution occurred. Refluxing was continued 4 hours longer. The. brown solutioniwas clarifiedxwith'. Nuchar, and the filtrate evaporated on a steam bath; Arresidue-of brownliquid and .solidremained. Concentrated. hydrochloric acid .was added andthe solid filtered, washed-with more. acid, and allowedto'dry. The material weighed 6.0. g. and decomposed at 188-'190 C. Crystallization from hot water raised the decomposition point to 197-198 C., and fusion-with the prey viously isolated 3-pheny-5-hydroxy-1,2;4eoxadiazoleof the samemelting'point gave no depres sion of the melting temperature. .In. this exame ple the hydrolysis was more drastic,'the starting material being converted first into 3-phenyl-5- amino-l,2,4,-oxadiazole and then to, 3-phenyl-5- hydroxy-1,2,4eoxadiazole without isolationv or the former as in Examples 1 and3. l -Iclaim:' J 1 1. A-,method,of preparing compounds having. thefollowing structural formula;

in whichR-is as defined above. I 7i 2. A method of preparing 3-alkyl-5-amino- 1,2 ,4-oxadiazoles which comprises heating in the presence of a'hydrolyzing agent a 3'-alkyl-5-'ur'eidoe1,2,4-' oxadiazole.- I

- .15 a. 'Am'ethodb! preaaaf iatslgmaatga 5 oxadiazoles which comprises heating in the presence of a hydrolyzing agent a 3-ary1-5-ureido- 1,2,4-oxadiazole.

4. A method of preparing 3-e1ky1-5-amino- 1,2,4-oxadiazo1es which comprises heating at a 5 6 6. A method of preparing 3-ary1-5-amino-1,2,4- oxadiazoles which comprises heating at a temperature withinthe range of 25-125 C. in the presence of water and an alkali a 3-ary1-5-ureido- 1,2,4-oxadiazo1e.

7 A method of preparing 3-ary1-5-amino-L2A- .oxadiazoles which comprises heating at a, temperature the range of 25-125 C. in the presence of water and barium hydroxide a 3-ary1- 10 S-ureido-1,2,4-oxadiazo1e.

DONALD W. KAISER. 

